2. Academic Validation
  3. ZLY032 mediated activation of Notch1/Hes1 signaling inhibits cardiomyocyte ferroptosis to protect against myocardial Ischemia-Reperfusion injury in mice

ZLY032 mediated activation of Notch1/Hes1 signaling inhibits cardiomyocyte ferroptosis to protect against myocardial Ischemia-Reperfusion injury in mice

  • Biochem Pharmacol. 2025 Sep:239:117039. doi: 10.1016/j.bcp.2025.117039.
Hao-Dong Li 1,  Dong-Ping Liu 1,  Man-Yu Gong 1,  Ying Zhang 1,  Jie Liu 1,  Jun-Ting Ren 1,  Meng-Xing Cheng 1,  Yan-Wei Zhang 1,  Hao Wang 1,  Si-Yu Wang 1,  Jian Huang 2,  Xue Feng 3,  Sen-Qing Jiang 3,  Xin Li 4,  Tong Liu 1,  Ming-Yu Yang 1,  Wei Liu 1,  Lei Jiao 5,  Meng-Meng Li 6,  Ying Zhang 7
Affiliations

Affiliations

  • 1 Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, China.
  • 2 The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
  • 3 Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 4 Department of Cardiovascular Sciences, School of Engineering, University of Leicester, Leicester, UK.
  • 5 Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, China. Electronic address: jiaolei116@163.com.
  • 6 Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China. Electronic address: 895544126@qq.com.
  • 7 Ultrasound Imaging Department of the Second Affiliated Hospital of Harbin Medical University, and State-Province Key Laboratories of Biomedicine-Pharmaceutics, College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang 150081, China. Electronic address: jennying223@hrbmu.edu.cn.
PMID: 40499841 DOI: 10.1016/j.bcp.2025.117039
Abstract

Myocardial ischemia/reperfusion (I/R) injury seriously compromises patients' prognosis and survival rates. Accumulating evidence shows that Ferroptosis is intricately involved in myocardial I/R injury. The activation of Notch1 exerts a protective effect on the heart. However, whether it plays a cardioprotective role by inhibiting cardiomyocyte Ferroptosis and what the underlying mechanisms are remain unclear. Here, we found that activating the Notch1/Hes1 signaling pathway during the ischemia/reperfusion (I/R) can effectively inhibit the levels of lipid peroxidation and oxidative stress in cardiomyocytes, thereby suppressing myocardial Ferroptosis. In addition, we identified a small molecule compound, ZLY032, which is an agonist of PPARδ and possesses anti-inflammatory and antioxidant activities. Treatment with ZLY032 potently alleviated I/R-mediated cardiac contractile impairment, decreased the infarct area and mitigated cardiomyocyte Ferroptosis. Mechanistically, the Notch intracellular domain (NICD)interacts with GPX4 to inhibit its degradation. As a PPARδ Agonist, ZLY032 activates the Notch1/Hes1 signaling pathway in a PPARδ-dependent manner, thereby inhibiting myocardial Ferroptosis and exerting a cardioprotective effect. In conclusion, our study elucidates that Notch1 inhibits cardiomyocyte Ferroptosis by modulating the protein stability of GPX4. Moreover, ZLY032 serves as a novel protective agent against myocardial ischemia-reperfusion injury， exerts its effects by relying on PPARδ-mediated upregulation of the Notch1/Hes1 signaling pathway and the subsequent reinforcement of GPX4 protein stability, highlighting the potential of ZLY032 as a promising therapeutic agent for treating myocardial I/R injury.

Keywords

Ferroptosis; GPX4; Myocardial ischemia/reperfusion injury; Notch1; PPARδ; ZLY032.

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